16-dialkylaminomethyl-b-norsteroids and salts thereof



United States Patent 3,488,738 16-DIALKYLAMINOMETHYL-B-NORSTEROIDS AND SALTS THEREOF Kenneth G. Holden, Stratford, NJ., and James F. Kerwin,

Broomall, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed June 9, 1964, Ser. No. 373,877 Int. Cl. C07c 171/06, 167/34; A61k 17/00 US. Cl. 260-563 Claims ABSTRACT OF THE DISCLOSURE This invention relates to new 16-substituted B-norsteroids having pharmacodynamic activity. More specifically these compounds are useful in having hypotensive, central nervous system depressant and antiandrogenic activi ties as well as being intermediates for preparing other B-norsteroids having like activities.

Representative of the compounds of this invention are those represented by the following structural formulas:

Formula 1 in which X represents 3,488,738 Patented Jan. 6, 1970 R represents methyl, methylene or preferably R represents methyl or hydroxymethyl; R represents methyl, hydroxymethyl or hydrogen; and R and R are lower alkyl, preferably methyl or ethyl, or taken together with the nitrogen atom, are pyrrolidino, piperidino, morpholino or N-lower alkyl piperazino. The 17ame thyl-17 -hydroxy isomers of the compounds described herein, i.e., the B-nortestosterone series, are preferred. The

group as so defined is generically referred to herein as a dialkylamino residue.

This invention also includes the pharmaceutically acceptable acid addition salts of the compounds of Formulas 1 and 2 in which R is a basic residue. Such salts are those with nontoxic organic and inorganic acids such as hydrochloric, hydrbromic, acetic, lactic, sulfamic, methylsulfonic, ethane-disulfonic, phosphoric, sulfuric, maleic, etc., acids. For use as intermediates other medicinally unacceptable salts may be used. These basic compounds can also be converted to their nontoxic, pharmaceutically acceptable quaternary ammonium salts with active quaternizing agents known to the art. Such agents may be active lower alkyl or aralkyl halide, sulfate or aryl sulfonate esters of a maximum of 8 carbon atoms, for example, lower alkyl halides, i.e., chlorides, iodides or bromides, lower alkyl sulfates, lower alkyl benzenesulfonates, benzyl chloride or bromide. The basic compounds of this invention can also be converted into their N-oxide derivatives if desired such as by oxidation with hydrogen peroxide in suitable organic solvents such as methanol.

The acid addition or quaternary ammonium salts of this invention are prepared by methods well known to the art; for example by reacting the basic steroid with an excess of the desired acid or quaternizing agent in an inert polar solvent at room temperature or in the case of the quaternaries at reflux. The salts usually separate from non-polar solvents readily. The quaternary salts possess pronounced hypotensive activity.

This invention also includes O-acylates of the hydroxyl containing B-norsteroids of this invention, Such O-acylates are those derived from pharmaceutically acceptable carboxylic acids of a maximum of 8 carbon atoms such as O-acetates, propionates, etc. The acylate derivatives are prepared as known to the art, for example, by heating at reflux in an excess of the anhydride such as acetic anhydride with or without an inert organic solvent or a tertiary amine base.

3 The compounds of this invention are prepared by the reactions outlined hereafter or variations of these processes obvious to those skilled in the art.

R1 R1 CHzN\ l B4 HO HO R1 -CH2 OH O R: -0H2N CH;

HO HO OH OH /R: R2 CHzN CH3 R2 CH In this reaction sequence R R and R are as defined above. R is methyl or hydroxymethyl except as explained hereafter; R is methyl or ethyl.

The compounds of this invention are prepared by reacting an appropriate B-nordehydroepiandrosteroue 3 with 9. formaldehyde source such as paraformaldehyde and a secondary amine or an acid addition salt thereof usually in an inert organic solvent such as isoamyl alcohol, benzene, toluene, ethyl acetate, ethers, etc. at reflux. The free amine and its acid addition salts are used equally well. The resulting product is a 16-dialkylaminomethyl- B-nordehydroepiandrosterone 4.

The Mannich intermediate 4 is then reacted with a metal alkylating agent for example a Grignard reagent such as methyl or ethyl magnesium halide or a lower alkyl lithium reagent such as methyl or ethyl lithium in an inert non-polar solvent, for example, ether, benzene, tetrahydrofuran or mixtures thereof. The resulting product is a mixture of 17-alkyl-17-hydroxy-16-dialkylaminomethyl isomers 5 but predominately the a-isomer. The isomers are separated if desired then oxidized such as by using an Oppenauer reaction to the desired 16a or )3- dialkylaminomethyl-17a-alkyl-B-nortestosterone 6'.

The 16,8-methyl-B-nortestosterones are prepared by decomposing the or fi-dialkylaminomethyl-B-nordehydroepiandrosterone Mannich intermediates 4 usually by steam distillation to the 16-methylene derivative 7 which is in turn hydrogenated catalytically to the 16-;3-methyl compound 8 then reacted with a Grignard or alkyl lithium reagent and oxidized at position 3 as described above.

The 19-nor-B-nortestosterone compounds of this invention (R =H) are conveniently prepared from 318,19- dihydroxy B norandrost-5-en-17-one (FIGURE 3, R =hydroxymethyl) via the Mannich reaction to insert the lddialkylaminomethyl group, Grignard or alkyl lithium to insert the 17-alkyl-17-hydroxy group and oxidation at 3 as described above. The resulting intermediate is that of FIGURE 6, R=hydroxymethyl. The 10-hydroxymethyl group is then oxidized using chromium trioxide-pyridine reagent, decarboxylated to the the 5,10- ene and isomerized to the desired 19-nor compound.

The 16-methylene and 16-methyl-19-nor congeners are similarly prepared by the following reactions.

/ --CH2N(CH )2 HOCHz CH: -K

HOCHz HOCHZ O OH i I l --GH' C 3 CH3 HO HO HOCHz 11 HO- [OX] In the above description the term lower alkyl refers to alkyl groups having a maximum of 8 carbon atoms preferably methyl or ethyl. The 16-substituents can be epimerized by treating the 17-keto intermediates gently with dilute alkali or acid. The following examples are intended to illustrate this invention to those skilled in the art but not to limit the scope of this invention.

EXAMPLE 1 A mixture of 5.0 g. of B-nordehydroepiandrosterone (3, R=methyl), 2.7 g. of paraformaldehyde, 9.0 g. of anhydrous dimethylamine hydrochloride and 40 ml. of dry isoamyl alcohol is heated at reflux with stirring under nitrogen for 2 hours. After standing at 5 C. for 16 hours the reaction mixture is poured into 5% aqueous ammonium hydroxide and extracted with methylene chloride. The dried methylene chloride extracts are evaporated under reduced pressure until the methylene chloride no longer distills. The residue is diluted with an equal volume of ether and cooled. The resulting precipitate is collected by filtration and recrystallized from methanol-ether-hexane to give l6u-dimethylaminomethyl- B-nordehydroepiandrosterone, M.P. 177-179 C.

EXAMPLE 2 To a solution of 5.2 g. of Mat-dimethylaminomethyl- B-nordehydroepiandrosterone in 300 ml. of benzene is added 35 ml. of 3 M methyl magnesium bromide in ether-benzene. The addition is carried out slowly with stirring under nitrogen. When addition is complete, the reaction mixture is heated at reflux for 2 hours, cooled, and poured into cold dilute hydrochloric acid. The organic phase is separated and the aqueous phase is washed with ether. After making the aqueous phase alkaline with sodium carbonate it is extracted with methylene chloride. The methylene chloride extracts are combined, dried and evaporated to a residue which is dissolved in benzene and chromatographed on 90 g. of alumina (activity III Woelm). Elution with benzene gives 35,170:- dihydroxy 16oz dimethylaminomethyl-17/3-methyl-B- norandrost-5-ene, M.P. 134136 C. after recrystallization from ether-petroleum ether. Elution with methylene chloride gives 3B,17,6-dihydroxy-l(Se-dimethylaminomethyl-l7ot-methyl B norandrost-S-ene, M.P. l76-178 C. after recrystallization from ether-petroleum ether.

EXAMPLE 3 A solution of 3.2 g. of 3/8,l7a-dihydroxy-lfia-dimethylaminomethyl-l7B-methyl-B-norandrost-5-ene in 400 ml. of toluene containing 42 ml. of cyclohexanone and 2.2 g. of aluminum isopropoxide is slowly distilled during 3 hours so that the volume of the reaction mixture is reduced to about 100 ml. The cooled reaction mixture is treated with 5 ml. of water, filtered and the filtrate steam distilled until the distillate is clear. Extraction of the cooled nonvolatile aqueous mixture with methylene chloride yields 17a-hydroxy 16a dimethylaminomethyl 17,9 methyl B norandrost-4-en-3-one, M.P. 125-127 C. after recrystallization from acetone-hexane. By the same method 3,9, 175 dihydroxy 16a dimethylaminomethyl 17oz. methyl-B-norandrost 5 ene yields 16a dimethylaminomethyl-l7a-methyl-B-nortestosterone, M.P. l56-157 C. after recrystallization from acetone-hexane.

This base (1.5 g.) is dissolved in ether and aliquots reacted with an excess of dry hydrogen chloride gas, maleic acid, sulfuric acid and ethane disulfonic acid to give the respective salts. The base (500 mg.) in ethyl acetate is heated at reflux with an excess of ethyl iodide for several hours. Concentration and trituration with ether gives the ethiodide salt.

EXAMPLE 4 A solution of 9.0 g. of 16a-dimethylaminomethyl-B- nordehydroepiandrosterone in 200 ml. of ethyl alcohol is steam distilled until the distillate is no longer basic. The cooled nonvolatile aqueous mixture is extracted with methylene chloride. The methylene chloride extracts are combined, dried, and evaporated to a residue. Chromatography of the residue on 150 g. of alumina (activity III Woelm) gives l6-methy1ene-B-nordehydroepiandrosterone on elution with benzene, M.P. 121-122 C. after recrystallization from acetone-hexane.

EXAMPLE 5 A solution of 1.0 g. of l6-methylene-B-nordehydroepiandrosterone in 50 ml. of alcohol is hydrogenated at 15 lb./sq. in. for 30 minutes in the presence of 0.2 g. of 10% palladium-on-charcoal. The reaction mixture is filtered and the filtrate evaporated to a residue. Recrystallization of the residue from acetone-hexane gives 16,9- methyl-B-nordehydroepiandrosterone, M.P. 132-134 C.

EXAMPLE 6 To a solution of 10.0 g. of 16,8-methyl-B-nordehydroepiandrosterone in 200 ml. of benzene is added 110 ml. of 3 M methyl magnesium bromide solution in etherbenzene. The addition is carried out slowly with stirring and cooling under nitrogen. After one hour at room temperature the reaction mixture is heated to reflux for an additional hour, cooled and poured into a cold aqueous solution of ammonium chloride and hydrochloric acid. The benzene layer is separated and the aqueous layer is extracted with methylene chloride. Evaporation of the combined and dried organic phases gives 3,8,17B-dihydroxy-lfifl,17a-dimethyl-B-norandrost 5 ene, M.P. l88- 197 C. after recrystallization from acetone-hexane.

EXAMPLE 7 By the method of Example 3, 3fl,l7fl-dihydroxy-16fi, 17a-dirnethyl-B-norandrost-5-ene is converted to 163,170? dimethyl-B-nortestosterone, M.P. ISO-151 C. after recrystallization from acetone.

EXAMPLE 8 A mixture of 5.2 g. of 313,19-dihydroxy-B-norandrost- 5-en-17-one, 2.7 g. of paraformaldehyde, 9 g. of dimethylamine hydrochloride and 50 ml. of dry isoamyl alcohol is heated at reflux for 6 hours. After standing overnight the mixture is worked up as described in Example 1 to give 19 hydroxy 16oz dimethylaminomethyl B nordehydroepiandrosterone.

This compound (2.8 g.) is reacted with 19 ml. of 3 M. methyl Grignard reagent in ether-benzene. After reaction and isolation as described 3,8,17a,19-trihydroxy-16adimethylaminomethyl-l7a-methyl-B-norandrost 5 ene is recovered along with its 17fi-hydroxy-17a-methyl isomer.

To 35 ml. of pyridine is added 3.5 g. of chromium trioxide with cooling and stirring. To the resulting mixture is added 3.0 g. of the crude 1713-hydroxy-17a-methyl isomer in 35 ml. of pyridine. After 24 hours at room temperature the reaction mixture is poured into water, concentrated at reduced pressure, cooled and filtered to give 16a-dimethylaminomethyl-17fl-hydroxy 17a methyl-3- oxo-B-norandrost-S-en-19-oic acid. This crude acid is dissolved in pyridine and heated at reflux for 2 hours. The pyridine is evaporated in vacuo to leave a residue of 16adimethylaminomethyl-l7B-hydroxy-17a methyl 19-nor- B-norandrost-5-(l0)-en-3-one. The residue is heated on the steam bath in methanol containing a trace of sodium hydroxide. The cooled mixture is quenched in water and extracted with methylene chloride. Drying and evaporation of the extracts gives a residue which may optionally be purified over alumina to give Mot-dimethylaminomethyl-17a-methy1-19-nor-B-nortestosterone.

A sample (200 mg.) of the base in ether-benzene is treated with dry hydrogen bromide gas to separate the hydrobromide salt.

EXAMPLE 9 A solution of 3 g. of 16-methylene-B-nordehydroepianrosterone in ml. of tetrahydrofuran is treated with 3 molar equivalents of stock methyl lithium-ether solution at room temperature with stirring under a nitrogen atmosphere. When the addition is complete the reaction mixture is refluxed for 2 hours, cooled, poured into volumes of water and extracted with methylene chloride. Evaporation of the dried methylene chloride extracts gives a residue of 3,3,l7fi-hydr0xy-17amethyl-l6-methylene-B- norandrost-S-ene, which is in turn oxidized using aluminum isoproxide and cyclohexanone as in Example 3 to give 17a-methyl-16-methylene-B-nortestosterone.

EXAMPLE 10 What is claimed is: 1. A compound of the formula:

in which X is O OH CH3 [1 a e OH C2115 R is diloweralkyl aminomethyl; R is methyl or hydromethyl and R is methyl, hydroxymethyl or hydrogen.

2. 16a-dirnethylaminomethyl-l7u-methyl-B nortestosterone.

3. l6u-dimethylaminomethyl-35,17/3 dihydroxy 17amethyl-B-norandrost-S-ene.

4. 16oz dimethylaminomethyl 17cc methyl ,8 nortestosterone hydrochloride.

5. 16a-dimethylaminomethyl 17a methyl-19-n0r-B- nortestosterone References Cited UNITED STATES PATENTS 3,375,280 3/1968 Holden 260-563 ROBERT V. HINES, Primary Examiner U.S. Cl. X.R. 

